Corticotropin releasing hormone (CRH) also referred to as corticotropin releasing factor (CRF) is one of the main signaling molecules of the hypothalamic pituitary adrenal (HPA) axis. CRH has a myriad of physiological effects that include behavioral, endocrine, autonomic and immune responses. CRH acts mainly by binding to CRH receptors type 1 (CRHR1) and type 2 (CRHR2) with a 10-fold affinity for the CRHR1 versus CRHR2. CRH receptors belong to the superfamily of G-protein coupled receptors and typically effect cellular activity via coupling to adenylate cyclase. CRHR1 is abundant in the brain, in adrenal glands, uterine and colonic tissues, and lymphocytes, for example. Eleven splice variants of the CRHR1 receptor have been identified, each with a tissue specific expression pattern. In addition, the naturally-produced CRH paralog, urocortin 1 (UCN1) can bind and activate both the CRHR1 and CRHR2. CRH is released in response to stress. CRH can affect nervous and visceral tissues such as the uterus and gut via activation of the two types of CRH receptors.
Due to the variety of physiological activities that the CRH system exerts, CRHR1 antagonists have been clinically used for more than three decades for a variety of conditions. For example, CRHR1 antagonists have been tested for the treatment of disorders including depression and irritable bowel syndrome (IBS). CRHR1 antagonists are proposed as a possible treatment for anxiety disorders. In fact, phase II/III clinical trials are ongoing or have been completed for depression, IBS and anxiety.
Antalarmin is a CRHR1 antagonist that has been investigated in animal research for its effects on reproduction, inflammation, addictive disorders, sleep disorders, among others. Antalarmin is a non-peptide molecule that readily crosses the blood-brain-barrier. Both anti-stress and anti-inflammatory activities of antalarmin have been documented in animal studies.
Endometriosis is a disorder in which endometrial tissue is found outside the uterus causing pain, infertility and stress. Finding an effective and long-term treatment for endometriosis still remains one of the most significant challenges in the field of obstetrics and gynecology.
Endometriosis is a chronic inflammatory disorder defined as the presence of endometrial-like tissue (e.g., glands and stroma) outside the endometrial cavity. This condition is characterized by peritoneal inflammation resulting in severe and chronic pelvic pain, and increases risk of infertility. Endometriosis is commonly misdiagnosed as irritable bowel syndrome (IBS) due to overlap in common symptoms, and perhaps because mechanisms of disease progression involve aberrant activation of inflammatory cascades. The causes of endometriosis onset are unknown; however, a relationship between stress, hypothalamic pituitary adrenal axis (HPA) dysregulation, and endometriosis severity has been reported based on investigations in a rat model.
Reports from human and animal studies, suggest that abnormal functioning of the HPA axis, and the release of CRH and/or the inflammatory response system, disrupts feedback of both neuroendocrine and immune systems, contributing to the development of endometriosis. Indeed, CRH and CRH receptors are abundant in female reproductive tissues. This axis has been shown to regulate several reproductive functions, mostly mediating pro-inflammatory activities such as ovulation, luteolysis, and blastocyst implantation. Despite the documented role of CRH receptors in stress related disorders, reproductive function, and inflammation, a role of the CRHR1 blockade in the treatment of endometriosis, is not established.